Clinical distribution of carbapenem genotypes and resistance to ceftazidime-avibactam in Enterobacteriaceae bacteria.

Introduction: Bacterial resistance is a major threat to public health worldwide. To gain an understanding of the clinical infection distribution, drug resistance information, and genotype of CRE in Dongguan, China, as well as the resistance of relevant genotypes to CAZ-AVI, this research aims to improve drug resistance monitoring information in Dongguan and provide a reliable basis for the clinical control and treatment of CRE infection. Methods: VITEK-2 Compact automatic analyzer was utilized to identify 516 strains of CRE collected from January 2017 to June 2023. To determine drug sensitivity, the K-B method, E-test, and MIC methods were used. From June 2022 to June 2023, 80 CRE strains were selected, and GeneXpert Carba-R was used to detect and identify the genotype of the carbapenemase present in the collected CRE strains. An in-depth analysis was conducted on the CAZ-AVI in vitro drug sensitivity activity of various genotypes of CRE, and the results were statistically evaluated using SPSS 23.0 and WHONET 5.6 software. Results: This study identified 516 CRE strains, with the majority (70.16%) being K.pneumoniae, followed by E.coli (18.99%). Respiratory specimens had highest detection rate with 53.77% identified, whereas urine specimens had the second highest detection rate with 17.99%. From June 2022 to June 2023, 95% of the strains tested using the CRE GeneXpert Carba-R assay possessed carbapenemase genes, of which 32.5% were blaNDM strains and 61.25% blaKPC strains. The results showed that CRE strains containing blaKPC had a significantly higher rate of resistance to amikacin, cefepime, and aztreonam than those harboring blaNDM. Conclusions: The CRE strains isolated from Dongguan region demonstrated a high resistance rate to various antibiotics used in clinical practice but a low resistance rate to tigecycline. These strains produce Class A serine carbapenemases and Class B metals ß-lactamases, with the majority of them carrying blaNDM and blaKPC. Notably, CRE strains with blaKPC and blaNDM had significantly lower resistance rates to tigecycline. CAZ-AVI showed a good sensitivity rate with no resistance to CRE strains carrying blaKPC. Therefore, CAZ-AVI and tigecycline should be used as a guide for rational use of antibiotics in clinical practice to effectively treat CRE.

Enhanced anticancer synergy of LOM612 in combination with selinexor: FOXO1 nuclear translocation-mediated inhibition of Wnt/ß-catenin signaling pathway in breast cancer.

BACKGROUND: The intricate relationship between Forkhead box O1 (FOXO1), a well-established tumor suppressor, and breast cancer (BC) remains partially elucidated. This study aims to investigate the mechanistic role of FOXO1 nuclear localization in the context of BC. METHODS: In vitro experiments employed BC cell lines MCF-7 and MDA-MB-175 treated with LOM612, a small molecule activator of FOXO nuclear-cytoplasmic shuttling, and selinexor, an exportin 1 inhibitor. Nuclear accumulation of FOXO1, its interaction with ß-catenin, and expressions of key proteins like V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), cyclin D1 and apoptosis markers were assessed. In vivo, the effects of LOM612 and selinexor were studied using MCF-7 cell-derived xenografts (CDX). RESULTS: Treatment with LOM612 exhibited a significant enhancement in nuclear accumulation of FOXO1 within BC cells. This effect coincided with suppressed migratory behavior and heightened apoptosis susceptibility in these cells. Mechanistically, LOM612 orchestrated FOXO1 to compete with transcription factors (TCF) for binding to ß-catenin in the nucleus, leading to reduced c-Myc and cyclin D1 expressions, along with elevated levels of apoptosis-related proteins. Similar trends were observed in CDX models, where LOM612 effectively suppressed tumor growth, increased FOXO1 nuclear localization, and downregulated c-Myc and cyclin D1 expressions. Importantly, selinexor synergistically reinforced the therapeutic effects of LOM612 both in vitro and in vivo. CONCLUSIONS: Collectively, this study underscores the potential of combining LOM612 and selinexor as an efficacious anti-BC strategy. The underlying mechanism involves FOXO1's nuclear translocation, which disrupts TCF-ß-catenin interactions, thus indirectly inhibiting the Wnt/ß-catenin signaling pathway.

Harnessing joint distraction for the treatment of osteoarthritis: a bibliometric and visualized analysis.

Osteoarthritis (OA) stands as a prevalent degenerative joint ailment, demanding immediate attention towards the development of efficacious therapeutic interventions. Presently, a definitive cure for OA remains elusive, and when conservative treatment modalities prove ineffective, resorting to a joint prosthesis becomes imperative. Temporary distraction emerges as a pivotal joint-preserving intervention in human OA patients, conferring both clinical amelioration and structural enhancements. Although extant clinical investigations exist, they are characterized by relatively modest sample sizes. Nonetheless, these studies furnish compelling evidence affirming that joint distraction engenders sustained clinical amelioration and structural refinement. Despite substantial strides in the last decade, a bibliometric analysis of joint distraction within the realm of osteoarthritis treatment research has been conspicuously absent. In this context, we have undertaken a comparative investigation utilizing bibliometric methodologies to scrutinize the landscape of joint distraction within osteoarthritis treatment. Our comprehensive analysis encompassed 469 scholarly articles. Our findings evince a consistent escalation in global research interest and publication output pertaining to this subject. The United States emerged as the frontrunner in international collaboration, publication count, and citation frequency, underscoring its preeminence in this domain. The journal "Osteoarthritis and Cartilage" emerged as the principal platform for disseminating research output on this subject. Notably, Mastbergen SC emerged as the most prolific contributor in terms of authorship. The identified keywords predominantly revolved around non-surgical interventions and joint arthroscopy procedures. This bibliometric analysis, augmented by visual representations, furnishes invaluable insights into the evolutionary trajectory of joint distraction as an osteoarthritis treatment modality spanning from 2003 to 2023. These insights will serve as a compass for the scientific community, facilitating further exploration in this promising domain.

Selinexor improves the anti-cancer effect of tucidinostat on TP53 wild-type breast cancer.

Histone deacetylase (HDAC) is closely related to the initiation and development of breast cancer (BC). Its inhibitor (HDACi) has been used to treat BC, while the efficacy of clinical trials was not reached expectations. HDACi combined with other drugs may be an effective strategy. This study explored the effect of HDACi tucidinostat combined with selinexor, an exportin 1 (XPO1) inhibitor, on ER+Her2- BC cell lines of MCF-7 (wt-TP53), MDA-MB-175 (wt-TP53), MDA-MB-134 (mut-TP53) and T47D (mut-TP53) in vitro and cell derived xenografts (CDX) of MCF-7 in nude mice in vivo. Results showed that both tucidinostat and selinexor showed better inhibitory activities on wt-TP53 BC (MCF-7 and MDA-MB-175) comparing with mut-TP53 BC (MDA-MB-134 and T47D). Tucidinostat combined with selinexor significantly improved the effects of tucidinostat alone on the proliferation and invasion inhibitions and apoptosis promotions of MCF-7 and MDA-MB-175 cells in vitro. It also significantly enhanced the effects of tucidinostat on up-regulating the expression levels of acetyl-p53, nuclear p53, total p53, p21, Bax and Cleaved Caspase-3, and down-regulating the expression levels of Cyclin D1 and Bcl-2 in MCF-7 or MDA-MB-175 cells. Results consistent with in vitro were also obtained in CDX of MCF-7 in vivo. Taken together, we believe that tucidinostat and selinexor are potentially effective drug combinations for the treatment of wt-TP53 BC, and the molecular mechanism may be through enhancing the activity of p53 in the nucleus of BC cells to suppress proliferation and invasion and promote apoptosis.

[Clinical study for preoperative traction on impact of osteonecrosis of femoral head in patients with femoral neck fractures].

OBJECTIVE: To explore the impact of preoperative traction on the osteonecrosis of the femoral head (ONFH) in patients with femoral neck fractures. METHODS: Between February 2013 and May 2016, 120 patients with femoral neck fractures, who were treated with screw fixation, were collected. Sixty patients with fractures of Garden type Ⅰ and Ⅱ were non-displaced fracture group; 60 cases with fractures of Garden type Ⅲ and Ⅳ were displaced fracture group. The patients in 2 groups were randomly divided into traction and non-traction subgroups ( n=30). There was no significant difference in gender, age, injury mechanism, damage side, the time from injury to operation, and fracture classification between 2 subgroups ( P>0.05). Intracapsular pressure was recorded before operation. The quality of fracture reduction and the satisfaction ratio of screw implant were evaluated during operation. Visual analogue scale (VAS), Harris score, joint mobility, and the incidence of ONFH would be evaluated at 6 months, 1 year, and 2 years after operation. RESULTS: All incisions of 2 groups healed by first intention after operation. There was no infection or deep vein thrombosis of lower extremity. All patients were followed up 2 years. In displaced and non-displaced fracture groups, the intracapsular pressure of traction subgroups were higher than that of non-traction group ( P<0.05); the differences of the quality of fracture reduction and the satisfaction ratio of screw implant were not significant ( P>0.05) between 2 subgroups. At 6 months, 1 year, and 2 years after operation, VAS scores were higher in traction subgroup than in non-traction subgroup ( P<0.05); and the joint mobility and Harris scores were lower in traction subgroup than in non-traction subgroup ( P<0.05). X-ray films showed all fractures healed. Except for the non-displaced group at 6 months, the incidences of ONFH were higher in traction subgroup than in non-traction subgroup at other time points ( P< 0.05). CONCLUSION: Preoperative traction may increase the risk of ONFH, which can increase the intracapsular pressure and affect the blood supply of femoral head.

Use of Receiver Operating Characteristic (ROC) Curve Analysis for Tyrer-Cuzick and Gail in Breast Cancer Screening in Jiangxi Province, China.

BACKGROUND Breast cancer is a malignant tumor derived from breast gland epithelium. The screening and early diagnosis of breast cancer in high-risk populations can effectively suppress its threat to women's health and improve treatment efficiency, and thus has critical importance. Using various evaluation models, the present study evaluated cancer risk in 35-69-year-old women, and the usefulness of models in breast cancer prevention was compared. MATERIAL AND METHODS A total of 150 infiltrative breast cancer patients who were diagnosed with breast cancer at our hospital were recruited, along with 130 healthy women as the control group. A retrospective study was performed to collect information. The 5-year risk of breast cancer was evaluated using the Gail and Tyrer-Cuzick models. Diagnostic results were analyzed to plot ROC curves for comparing the value for screening between Gail and Tyrer-Cuzick models. RESULTS The Gail model has 53.33% sensitivity and 77.69% specificity, with 73.39% positive prediction value, 59.06% negative prediction value, 64.64% accuracy, and 0.31 Jordon index. The Tyrer-Cuzick model had 66.00% sensitivity, 86.92% specificity, 85.34% positive prediction value, 68.90% negative prediction value, 75.71% accuracy, and 0.53 Jordon index. The area under the curve (AUC) was 0.665 for the Gail model (95% CI: 0.629~0.701) and 0.786 for the Tyrer-Cuzick model (95% CI: 0.757~0.815). CONCLUSIONS Both Gail model and Tyrer-Cuzick models can be used to evaluate breast cancer risk. The Gail model has relatively lower accuracy in evaluating breast cancer risk in Jiangxi province of China and the Tyrer-Cuzick model had relatively higher accuracy.

[Resveratrol regulate the extracellular matrix expression via Wnt/ß-catenin pathway in nucleus pulposus cells].

Objective: To investigate the regulatory effect of resveratrol (RES) on the extracellular matrix (ECM) expression of nucleus pulposus cells (NPC), and its relative molecular mechanism. Methods: Ten patients receiving discectomy were collected, of which 5 patients were young with spinal burst fracture, classified as control group; the rest 5 patients were senile with lumbar disc herniation, classified as degenerative group. The nucleus pulposus tissue of 2 groups were collected, the in situexpression of ß-catenin was detected by immunohistochemistry, and the protein expressions of collagen type Ⅱ and Aggrecan were detected by Western blot. The NPC were isolated and cultured from degenerative nucleus pulposus tissues. RES treated the third-passage NPC with (group B) or without IL-1ß (group C), to further determine the protein expressions of collagen type Ⅱ and Aggrecan by Western blot, the unstimulated cells were set up as blank control group (group A). Moreover, NPC treated with small interfering RNA (siRNA) targeted silent SIRT1 or ß-catenin were used to determine the protein and gene expressions of ß-catenin and SIRT1 by Western blot and real-time fluorescence quantitative PCR. In addition, the third-passage NPC treated with complete medium (group 1), IL-1ß (group 2), RES+IL-1ß (group 3), and SIRT1-siRNA+RES+IL-1ß (group 4) for 24 hours were used to detect the nuclear translocation of ß-catenin by cell immunofluorescence staining. Finally, the third-passage NPC treated with complete medium (group Ⅰ), IL-1ß (group Ⅱ), IL-1ß+ß-catenin-siRNA (group Ⅲ), IL-1ß+RES (group Ⅳ), and IL-1ß+RES+SIRT1-siRNA (group Ⅴ) for 24 hours were used to detect the protein expressions of collagen type Ⅱ and Aggrecan by Western blot. Results: Immunohistochemical staining and Western blot detection showed that when compared with control group, the cell proportion of expression of ß-catenin were significantly increased in degenerative group ( t=4.616, P=0.010); the protein expression of ß-catenin was also significantly increased and the protein expressions of collagen type Ⅱ and Aggrecan were significantly decreased ( P<0.05). In cytology experiments, the protein expression of ß-catenin in group B was significantly higher than that in groups A and C, and the protein expressions of collagen type Ⅱ and Aggrecan in group B were significantly lower than those in groups A and C ( P<0.05). After transfection of siRNA, the protein expressions of SIRT1 and ß-catenin significantly decreased ( P<0.05). The results of cell immunofluorescence staining further confirmed that when compared with group 3, after the SIRT1 was silenced by siRNA in group 4, the attenuated nuclear translocation of ß-catenin by RES treatment was aggravated. Western blot results showed that the protein expressions of collagen type Ⅱ and Aggrecan in group Ⅱ were significantly lower than those in group Ⅰ( P<0.05); after transfection of ß-catenin-siRNA in group Ⅲ, the degradation of ECM by IL-1ß was obviously inhibited, the protein expressions of collagen type Ⅱ and Aggrecan were significantly increased when compared with group Ⅱ ( P<0.05); after transfection of SIRT1-siRNA in group Ⅴ, the protective effect of RES on the degradation of ECM was inhibited, the protein expressions of collagen type Ⅱ and Aggrecan were significantly decreased when compared with group Ⅳ ( P<0.05). Conclusion: RES regulates the ECM expression of NPC via Wnt/ß-catenin signaling pathway, which provide a new idea for intervertebral disc degeneration disease treatment.

Nerve growth factor delivery by ultrasound-mediated nanobubble destruction as a treatment for acute spinal cord injury in rats.

BACKGROUND: Spinal cord injuries (SCIs) can cause severe disability or death. Treatment options include surgical intervention, drug therapy, and stem cell transplantation. However, the efficacy of these methods for functional recovery remains unsatisfactory. PURPOSE: This study was conducted to explore the effect of ultrasound (US)-mediated destruction of poly(lactic-co-glycolic acid) (PLGA) nanobubbles (NBs) expressing nerve growth factor (NGF) (NGF/PLGA NBs) on nerve regeneration in rats following SCI. MATERIALS AND METHODS: Adult male Sprague Dawley rats were randomly divided into four treatment groups after Allen hit models of SCI were established. The groups were normal saline (NS) group, NGF and NBs group, NGF and US group, and NGF/PLGA NBs and US group. Histological changes after SCI were observed by hematoxylin and eosin staining. Neuron viability was determined by Nissl staining. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining was used to examine cell apoptosis. NGF gene and protein expressions were detected by quantitative reverse transcription polymerase chain reaction and Western blotting. Green fluorescent protein expression in the spinal cord was examined using an inverted fluorescence microscope. The recovery of neural function was determined using the Basso, Beattie, and Bresnahan test. RESULTS: NGF therapy using US-mediated NGF/PLGA NBs destruction significantly increased NGF expression, attenuated histological injury, decreased neuron loss, inhibited neuronal apoptosis in injured spinal cords, and increased BBB scores in rats with SCI. CONCLUSION: US-mediated NGF/PLGA NBs destruction effectively transfects the NGF gene into target tissues and has a significant effect on the injured spinal cord. The combination of US irradiation and gene therapy through NGF/PLGA NBs holds great promise for the future of nanomedicine and the development of noninvasive treatment options for SCI and other diseases.

IL-1ß induces apoptosis and autophagy via mitochondria pathway in human degenerative nucleus pulposus cells.

IL-1ß has been reported highly expressed in degenerative intervertebral disc, and our previous study indicated IL-1ß facilitates apoptosis of human degenerative nucleus pulposus (NP) cell. However, the underlying molecular mechanism remains unclear. We here demonstrate that IL-1ß played a significantly pro-apoptotic effect under serum deprivation. IL-1ß decreased Bcl-2/Bax ratio and enhanced cytochrome C released from mitochondria to cytosol, which proved mitochondria-meidated apoptosis was induced. Subsequently, mitochondria damage was detected under IL-1ß stimualtion. In addition, IL-1ß-mediated injuried mitochondria contributes to activate autophagy. However, pretreatment with the autophagy inhibitor 3-methyladenine showed the potential in further elevating the apoptosis rate induced by IL-1ß in NP cells. Our results indicated that the mitochondrial pathway was involved in IL-1ß-induced apoptosis of NP cells. Meanwhile, the damaged mitochondria-induced autophagy played a protective role against apoptosis, suggesting a postive feedback mechanism under inflammatory stress.

Microsurgery or open cervical foraminotomy for cervical radiculopathy? A systematic review.

OBJECTIVE: The purpose of this article was to systematically review the clinical outcomes of microendoscopic foraminotomy compared with the traditional open cervical foraminotomy. METHODS: A literature search of two databases was performed to identify investigations performed in the treatment of cervical foraminotomy with microsurgery or an open approach. Data including blood loss, surgical time, hospital stay, complications, clinical success rate, reduction of arm and neck pain, improvement of neurological function, and repeated surgery rate were summarized, calculated and compared. Results of clinical success were performed by calculattng effect indicators and standard errors based on a single rate to assess heterogeneity in the two groups. RESULTS: The initial literature search resulted in 713 articles, of which, 26 were determined as relevant on abstract review. An open foraminotomy approach was performed in 16 and a microsurgery approach in ten studies. The open group demonstrated minimal to moderate heterogeneity, with I (2) value of 27 %; and microsurgery group demonstrated minimal heterogeneity, with I (2) value of 1 %. Aggregated data found that patients treated by microsurgery foraminotomy have lower blood loss by 100.1 ml (open: 149.5 ml, microsurgery: 49.4 ml, n = 1257), shorter surgical time by 24.9 minutes (open 88.7 minutes, microsurgery 63.8 minutes, n = 1423),and shorter hospital stay by 3.0 days (open 4.1 days, microsurgery 1.1 days, n = 1350), compared with patients treated by open cervical foraminotomy. The pooled clinical success rate was 89.7 % [confidence interval (CI) 87.7-91.6) in the open group versus 92.5 % (CI 89.9-95.1) in the microsurgery group, with no statistical difference (p = 0.095). Overall complication rates were not statistically significant between groups (p = 0.757). The incidence of dural tears was 1.07 %( 12/1121) in patients undergoing microsurgery versus 0.27 % (2/745) for open surgery (p = 0.091). The incidence of infection was 0.54 % (6/1121) in patients undergoing microsurgery versus 0.40 % (3/745) for open surgery (p = 0.949). The incidence of root injury was 0.80 % (9/1121) in patients undergoing microsurgery versus 1.48 % (11/745) for open surgery (p = 0.166). Revision surgery occurred in 2.32 % (27/1163) in the microsurgery group versus 3.35 % (28/835) for traditional surgery, with no statistical difference (p = 0.164). Pooled reduction in visual analogue scale for the arm (VASA) was 75.0 % (CI 66.0-84.0) in the open group and 87.1 % (CI:76.7, 97.5) in the microsurgery group, with no statistical difference (p = 0.065). Pooled reduction in VAS of the neck (VASN) was 66.2 % (CI:52.2, 80.2) in the open group and 68.1 % (CI:36.4, 99.8) in the microsurgery group, with no statistical difference(p = 0.894). Pooled improvement in neurological function was 55.3 % (CI:18.6, 91.9) in the open group and 64.9 % (CI:34.6, 95.2) in the microsurgery group, with no statistical difference (p = 0.576). CONCLUSIONS: Although advantages of cervical microsurgery are less blood loss and shorter surgical time and hospital stay over the standard open technique, there is no significant difference in clinical success rate, complication rate, reduction of arm and neck pain and improvement of neurological function between microsurgery and open cervical foraminotomy.